Wang Huabin, Jin Xuanlin, Lin Fenfang, Chen Guangming, Lin Meili, Ma Yongjun
Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Renming Road, Jinhua city, 321000, Zhejiang Province, China.
Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Lipids Health Dis. 2025 Jun 7;24(1):205. doi: 10.1186/s12944-025-02632-4.
BACKGROUND: The role of high-density lipoprotein cholesterol (HDL-C) in diabetic kidney disease (DKD) remains controversial. This study aimed to delineate the subgroup-specific relationships between the two by exploring cumulative and threshold effects. METHODS: 3,040 patients with type 2 diabetes and no baseline evidence of DKD were included. Cox proportional hazards regression models were performed to investigate the potential relationship between HDL-C level and DKD risk. To address subgroup heterogeneity, sex-stratified restricted cubic splines (RCS) were employed to model nonlinear relationships. The optimal threshold was identified through the maximum selected statistics and validated via 1,000 bootstrap iterations. Subgroup analyses stratified by sex, diabetes duration, and metabolic status were performed to evaluate heterogeneity. Survival analysis using Kaplan-Meier curves further validated these threshold effects. RESULTS: During a median follow-up of 3.13 years, 665 subjects (21.9%) progressed to DKD. Overall, each 1 mmol/L increase in HDL-C level independently reduced DKD risk by 43%. RCS analysis demonstrated an inverse correlation between HDL-C and DKD risk (P for overall = 0.025, P for nonlinear = 0.317), with increased risk reduction at lower concentrations, plateauing at higher levels. A robust threshold of 0.93 mmol/L was identified, showing significantly stronger protection against DKD progression (hazard ratio (HR) = 0.69, P < 0.001) compared to the traditional cutoff (HR = 0.86, P = 0.109). Females showed continuous protection (HR = 0.41, P = 0.009) without threshold dependency. The male and diabetes duration < 10 years subgroups exhibited threshold effects at > 0.93 mmol/L without continuous protection. The metabolically unstable (hypertension, poorly controlled glycemia, body mass index (BMI) > 28 kg/m) and BMI < 24 kg/m² subgroups displayed dual effects (P < 0.05). Survival analysis confirmed lower cumulative DKD incidence with HDL-C > 0.93 mmol/L (P = 0.007). CONCLUSIONS: This study reveals sex- and metabolic context-dependent heterogeneity in HDL-C-DKD associations: males and short-duration diabetes exhibited threshold effects (0.93 mmol/L), females showed continuous protection, and subgroups with hypertension, poorly controlled glycemia, or obesity (BMI > 28 kg/m²) exhibited both continuous protection and threshold effects. These findings may inform individualized risk stratification in specific populations.
背景：高密度脂蛋白胆固醇（HDL-C）在糖尿病肾病（DKD）中的作用仍存在争议。本研究旨在通过探索累积效应和阈值效应来阐明两者在特定亚组中的关系。 方法：纳入3040例2型糖尿病患者，且这些患者在基线时无DKD证据。采用Cox比例风险回归模型研究HDL-C水平与DKD风险之间的潜在关系。为解决亚组异质性问题，采用按性别分层的受限立方样条（RCS）来模拟非线性关系。通过最大选择统计量确定最佳阈值，并通过1000次自抽样迭代进行验证。进行按性别、糖尿病病程和代谢状态分层的亚组分析以评估异质性。使用Kaplan-Meier曲线进行生存分析进一步验证了这些阈值效应。 结果：在中位随访3.13年期间，665名受试者（21.9%）进展为DKD。总体而言，HDL-C水平每升高1 mmol/L可独立降低DKD风险43%。RCS分析显示HDL-C与DKD风险呈负相关（总体P = 0.025，非线性P = 0.317），在较低浓度时风险降低增加，在较高水平时趋于平稳。确定了一个稳健的阈值为0.93 mmol/L，与传统切点相比，其对DKD进展的保护作用显著更强（风险比（HR）= 0.69，P < 0.001）（传统切点HR = 0.86，P = 0.109）。女性表现出持续保护作用（HR = 0.41，P = 0.009），且无阈值依赖性。男性和糖尿病病程<10年的亚组在>0.93 mmol/L时表现出阈值效应，但无持续保护作用。代谢不稳定（高血压、血糖控制不佳、体重指数（BMI）>28 kg/m²）和BMI<24 kg/m²的亚组表现出双重效应（P < 0.05）。生存分析证实HDL-C>0.93 mmol/L时DKD累积发病率较低（P = 0.007）。 结论：本研究揭示了HDL-C与DKD关联中存在性别和代谢背景依赖性异质性：男性和糖尿病病程短者表现出阈值效应（0.93 mmol/L），女性表现出持续保护作用，而高血压、血糖控制不佳或肥胖（BMI>28 kg/m²）亚组既表现出持续保护作用又表现出阈值效应。这些发现可能为特定人群的个体化风险分层提供参考。
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